ABSTRACT Fragility fractures of the hip, spine or wrist affect 1.5 million Americans annually and are a common cause of pain, deformity and disability. Moreover, caring for these fracture patients costs nearly $10 billion annually. Based on the assumption that fragility fractures are caused by low bone mass, the World Health Organization (WHO) has identified individuals at risk for these fractures based on their areal bone mineral density measured by dual energy X-ray absorptiometry (DXA) compared to that of a normal young adult. However, fracture predictions based on areal bone mineral density have been shown to be neither sensitive nor specific. Whole bone strength is determined by the material properties of the bone tissue and its geometry. Areal bone mineral dnesity does not measure volumetric bone mineral density, the major determinant of bone stiffness and strength, and does not distinguish changes in bone tissue composition from changes in bone tissue volume and/or geometry. This distinction is important when diagnosing and treating skeletal diseases associated with low bone mass. While it is assumed that most fragility fractures are caused by osteoporosis, where the mineral composition of the bone tissue is normal, but the volume of bone tissue is decreased; 50% of postmenopausal women who fracture their hip and have no other cause for low bone mass, are deficient in vitamin D. Vitamin D deficiency can result in osteomalacia, where the mineral composition and bone tissue volume are both decreased. Indeed, of patients with low bone mass who fractured their hip, when their bone tissue was evaluated histologically, 13-33% were osteomalaciac. Correct assessment of the underlying causes of osteopenia, whether osteoporosis or osteomalacia, is important, as the treatment protocols for these two conditions are different, where osteoporosis may be treated with Bisphosphonates, PTH, Calcium, phosphate and vitamin D supplementation; whereas osteomalacia requires a more detailed evaluation, as the differential diagnosis is extensive, and each disease entity requires a somewhat different treatment approach. Since the treatment of osteoporosis and osteomalacia are different, it is imperative that the etiology of a patient's low bone mass be properly diagnosed. Therefore, we propose to develop a MRI based technique capable of measuring both bone tissue mineral and matrix composition and bone structure. To that end, we hypothesize that liquid+solid state MR imaging can be used to: differentiate metabolic bone diseases on the basis of bone tissue mineral composition and structural properties; and estimate the load capacity of normal and pathologic bones. Successful completion of this study will prove the feasibility of using this non-invasive and non-ionizing imaging technique to differentiate osteoporosis from osteomalacia, so that physicians may select appropriate treatment for at risk patients. This will provide an impetus to develop specialized MRI software and hardware that will make it possible to integrate liquid+solid state MR imaging routinely into clinical scanners or specialized peripheral MRI scanners that can be used for mass screening of at risk patients. The immediate career goals of the applicant are to gain expertise in the field of liquid and solid state MR imaging, generate preliminary results in the proposed project, contribute to the body of knowledge, obtain foundation grants to continue work, and move towards independence as a scientist and a principal investigator. The applicant will be supervised closed by the mentor and the co-mentor over the course of the study via informal regular meetings and formal meetings every two months to assess the applicant's progress along the project timeline. Additionally, the applicant will receive hands on and theoretical training on MR imaging, and training in bone biology and pathophysiology. His training will be augmented by attending various seminars, grant writing workshops and leadership development workshops. An advisory committee made up of experienced scientists in the field (Drs. Boskey, Bouxsein, Glimcher and Neer) will monitor the applicant's progress through meetings every six months and will be tasked with assessing the applicant's readiness to move on to the independent phase of the award, based on the applicant's fulfillment of the following criteria: independent and solid foundation in MR imaging principles, coil building and tuning, bone biology and pathophysiology; progress in research project as per study timeline; submission of three manuscripts by the end of the mentored phase; submission of a foundation award proposal based on research work; and ability to think independently and plan out a R01 level grant proposal. The applicant will be required to design and submit a R01 grant at the beginning of year two of the independent phase to assure funding continuity. The applicants' career goal is to develop as an independent musculoskeletal investigator with expertise in bone biomechanics and imaging to achieve the ultimate public health aim of helping to reduce fragility fracture risk associated with skeletal pathologies and their impact on patients and the health care system. While DXA imaging has been a useful tool to raise awareness and assess fragility fracture risks in individuals at risk, the inherent limitations associated with this modality and the recent advances in skeletal solid and liquid state MR imaging have provided a fresh impetus to develop the next generation of diagnostic systems capable of accurately identifying the underlying cause(s) of altered skeletal states.